Synthesis And Characterization Of Nano-MRI Contrast Agents Based On Nitrogen Oxide

Early detection and accurate diagnosis of tumor are crucial to successful cancer therapy. Magnetic resonance imaging (MRI) has become one of the most important medical imaging technique in clinical because of high resolution in soft tissues imaging and no radiation, and it also plays an important role in early diagnosis and treatment monitoring. However, without contrast agent (CA) the sensitivity of MRI is low, so it is necessary to use CA to improve its sensitivity and accuracy in detection of disease. Both the currently used in clinical and under reseaching MRI contrast agents are lack of specifity for tumors, resulting in not ideal imaging effct because the contrast agent has imaging in both tumor and normal tissue. So the development of a tumor-specific MRI contrast agent to enhance sensitivity in detection of disease is of critical significance. Due to the different physiological characteristics between tumors and normal tissues, the design and development of tumor-specific contrast agents become possible. In particular, pH-responsive PEGylated nanogels address one of the obstacles for nano-contrast agents because the extrcellular of tumor tissues (pH 6.5-7.0) are known to have a slight acidic pH compared with normal tissues (pH 7.4). Additionally the design and development of anaerobic-targeted MRI contrast agent become possible because of highly hypoxic environment of tumor tissues compared with normal tissues.This thesis briefly introduced the methods of tumor diagnostic imaging, MRI and its principle, as well as the research progress and prospective directions of MRI contrast agents with the emphasis on biological responsive and polymer contrast agents. In the thesis, we designed a nanogel CA (NGCA) with exact molecular structure, long blood circulation time, high relaxation rate, and tumor microenvironment response.Contrast agents containing hydrophobic crosslinker molecules (HDA-DTPA-Gd3+) was synthesized and modified with hydrophilic VBPEG, plus introduce diethylaminoethyl methacrylate (DEAMA) through microemulsion polymerization, getting nanogel-MRI contrast agents, characteristic of pH-responsive and anaerobic targeted group (oxidation DEAMA) in the core and hydrophilic protective group outside the core after oxidation of hydrogen peroxide. Compared with different recipes and preparation conditions, we found that the synthesizedNGCA formed 34 nm stable nanoparticles and has a mean diameter of 66 nm after oxidized by H2O2 when pH=7.4 at mass ratio of VBPEG (3%)、DEAMA (57%)、HDA-DTPA-Gd3+(40%). It was found that the relaxivity (r1) of NGCA increase from 5.3 mM-1s-1 to 11.5mM-1s1 when pH value decrease from 6.8 to 6.0,2.6 times higher than that of DTPA-Gd3+(Magnevist(?)). The oxidized NGCA (ONGCA) show higher r1 compared with NGCA, result in ONGCA having tumor microenvironment (pH and anaerobic) responsiveness. In vivo imaging of animal experiments indicate that ONGCA could effectivly enhance tumor imaging under relatively low dose. At the meantime, we occasionally found that NGCA exhibit relatively high toxicity to both normal and cancer cells, while ONGCA exhibit relatively high toxicity to cancer cells and exhibit relatively low toxicity to normal cells. All the experiment result show we preliminary prepara a NGCA with tumor microenvironment (pH and anaerobic) responsiveness as well as antitumor effect in vitro. It is of great interest in becoming a contrast agents integrated diagnosis and treatment. The follow-up task consists of the anaerobic-response mechanism and the animal antitumor experiments of NGCA.